Functionalized cis- and trans-fused bicyclic α-amino acids via stereoselective double annulation and dequaternization reactions

Fused bicyclic α-amino acids can be prepared by a double Michael reaction of p-anisyl ethynyl ketone and a tethered diacid, cyclization via hydrogenation or hydration of a CN group, and oxidation of the p-anisyl group. The substitution level of the α-amino acids can be adjusted by decyanation or decarboethoxylation of the intermediates. Bicyclic α-amino acids prepared in this way include cis- and trans-perhydroisoquinoline-3-carboxylic acids and cis-perhydro-2-pyrindine-3-carboxylic acids of various substitutions and oxidation levels. The bicyclic α-amino acids may be regarded as functionalized and conformationally restricted analogues of proline, pipecolic acid, 2-aminoadipic acid, or glutamic acid.